Pathoadaptive Mutations in Treponema Pallidum, the Syphilis

梅毒螺旋体的病理适应性突变

• 批准号: 8303036
• 负责人: GLABER ARTURO CENTURION-LARA
• 金额: $ 19.29万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303036
• 关键词: Address; Archives; Central Nervous System Infections; Clinical; Code; Collection; DNA; Databases; Development; Epidemiology; Fingerprint; Foundations; Future; Gene Mutation; Gene Silencing; Genes; Genetic; Genetic Variation; Genome; Genomics; Geographic Locations; Globus Pallidus; Goals; Hot Spot; Human; Immune response; Immunology; Individual; Intercistronic Region; Knowledge; Laboratories; Maps; Methods; Modeling; Modification; Molecular; Molecular Profiling; Mutation; Neuraxis; Neurosyphilis; Nucleotides; Order Spirochaetales; Organism; Oryctolagus cuniculus; Pathogenesis; Patients; Phylogenetic Analysis; Phylogeny; Population; Positioning Attribute; Proteins; Public Health; Research; Sampling; Sexually Transmitted Diseases; Source; Specificity; Syphilis; Techniques; Testing; Tissues; Transcript; Treponema pallidum; Variant; Virulent; Work; base; body system; clinical phenotype; comparative; comparative genomics; cross immunity; genetic manipulation; genome sequencing; genome wide association study; genome-wide; genome-wide analysis; global health; insight; novel

DESCRIPTION (provided by applicant): Syphilis is a significant problem for global health. It is caused by Treponema pallidum subsp. pallidum (T. palidum), a highly virulent, invasive and intractable spirochete. The goal of this proposal is to use comparative genomics on a population-wide scale to determine the contribution of genetic mutations to the identification of T. pallidum strains associated with distinct tissue enrichments, to the development of a refined strain fingerprinting method and for genome-wide expression profiling. Comparative genome-wide analysis will be done on a number of T. pallidum isolates as well as more recent isolates originated from patients with distinct clinical presentations and diverse geographical distributions. The Specific Aims are as follows: 1. Determine the population genomic variability of T. pallidum isolates representing geographical and chronological diversity; 2. Identify repeated mutational changes (hot spot mutations) in T. pallidum. High-throughput de novo, state-of-the-art sequencing approaches will be used to obtain a comprehensive number of genome sequences from our collection of T. pallidum isolates. We will create a publicly available database that will include a genome-wide map of mutations acquired in T. pallidum. Targeted qRT-PCR analysis will be performed to determine impact of hot spots on transcript levels of selected genes. Overall, accomplishment of the proposed studies will set the basis for the advance of our understanding at the molecular level of the epidemiology of T. pallidum isolates. It will also lay the groundwork for futures studies on a large scale, population-wide association research between specific genetic variations and tissue/organ/system involvement, and for a better understanding at the molecular level of how treponemes can, for example, re-infect or super-infect individuals. These studies can have a far reaching impact on issues of clinical and public health significance. PUBLIC HEALTH RELEVANCE: Understanding the mechanisms Treponema pallidum uses to cause different clinical presentations and how this organism can re-infect or super-infect an individual will have a significant impact on public health. Furthermore, the studies will help to understand the epidemiology of syphilis.

描述（由申请人提供）：梅毒是全球健康的一个重大问题。它是由梅毒螺旋体亚种引起的。苍白球菌（T. palidum），一种高毒力、侵袭性和难治性螺旋体。该提案的目标是在人群范围内使用比较基因组学来确定基因突变对识别与不同组织富集相关的梅毒螺旋体菌株的贡献，对开发精细菌株指纹识别方法和基因组分析的贡献。广泛的表达谱。将对许多梅毒螺旋体分离株以及来自具有不同临床表现和不同地理分布的患者的最新分离株进行比较全基因组分析。 具体目标如下： 1. 确定代表地理和年代多样性的梅毒螺旋体分离株的群体基因组变异性； 2. 识别梅毒螺旋体中重复的突变变化（热点突变）。高通量从头、最先进的测序方法将用于从我们的梅毒螺旋体分离株收集中获得全面的基因组序列。我们将创建一个公开可用的数据库，其中包括梅毒螺旋体中获得的全基因组突变图谱。将进行靶向 qRT-PCR 分析，以确定热点对选定基因转录水平的影响。 总体而言，拟议研究的完成将为我们在分子水平上进一步了解梅毒螺旋体分离株的流行病学奠定基础。它还将为未来进行大规模、全人群特定遗传变异与组织/器官/系统参与之间的关联研究奠定基础，并在分子水平上更好地理解密螺旋体如何重新感染或超级感染个体。这些研究可以对具有临床和公共卫生意义的问题产生深远的影响。 公共卫生相关性：了解梅毒螺旋体引起不同临床表现的机制以及这种生物体如何重新感染或重复感染个体将对公共卫生产生重大影响。此外，这些研究将有助于了解梅毒的流行病学。